Abstract
The cellular and molecular basis of stromal cell recruitment, activation and crosstalk in carcinomas is poorly understood, limiting the development of targeted anti-stromal therapies. In mouse models of triple negative breast cancer (TNBC), Hedgehog ligand produced by neoplastic cells reprograms cancer-associated fibroblasts (CAFs) to provide a supportive niche for the acquisition of a chemo-resistant, cancer stem cell (CSC) phenotype via FGF5 expression and production of fibrillar collagen. Stromal treatment of patient-derived xenografts with smoothened inhibitors (SMOi) downregulates CSC markers expression and sensitizes tumors to docetaxel, leading to markedly improved survival and reduced metastatic burden. In the phase I clinical trial EDALINE, 3 of 12 patients with metastatic TNBC derived clinical benefit from combination therapy with the SMOi Sonidegib and docetaxel chemotherapy, with one patient experiencing a complete response. These studies identify Hedgehog signaling to CAFs as a novel mediator of CSC plasticity and an exciting new therapeutic target in TNBC.
Highlights
The cellular and molecular basis of stromal cell recruitment, activation and crosstalk in carcinomas is poorly understood, limiting the development of targeted anti-stromal therapies
M6-Ctrl and M6-Hh monoculture cell viability were similar between vehicle and smoothened inhibitors (SMOi) treatment and the expression of canonical Hh target genes Ptch, Gli[1], and Hhip were downregulated in vivo but not in vitro, consistent with a paracrine requirement for Hh signaling as previously reported[6,12,13] (Supplementary Fig. 1e–g)
In certain settings, cancer stem cell (CSC) are responsible for metastasis to distant organs[32,33,34] and are frequently enriched in residual tumors following chemotherapy[35,36,37], reflecting a role in therapeutic resistance
Summary
The cellular and molecular basis of stromal cell recruitment, activation and crosstalk in carcinomas is poorly understood, limiting the development of targeted anti-stromal therapies. In the phase I clinical trial EDALINE, 3 of 12 patients with metastatic TNBC derived clinical benefit from combination therapy with the SMOi Sonidegib and docetaxel chemotherapy, with one patient experiencing a complete response These studies identify Hedgehog signaling to CAFs as a novel mediator of CSC plasticity and an exciting new therapeutic target in TNBC. Cell fate specification occurs through activation of transcriptional cascades in response to extracellular signals from developmental signaling pathways such as Hedgehog (Hh), Wnt, Notch, BMP (bone morphogenetic proteins), and FGF (fibroblast growth factor)[1,2]. While it is apparent that Hh signals in a paracrine manner in animal models of TNBC6 and in isolated cancer stem cells (CSCs)[12], a detailed study of the dynamic crosstalk within the TME is required to make clinical progress in integrating antistromal therapies into breast cancer treatment. SMOi treatment sensitized tumors to docetaxel chemotherapy in mouse models and in patients from the EDALINE Phase I clinical trial, resulting in reduced metastatic burden and improved survival
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